There are at least 26 novel therapies in the mitral valve repair race. But slow trials and questions about their stand-alone impact remain issues in this space.

CHICAGO, IL—There are at least 26 novel devices vying to prove their mettle in the transcatheter mitral valve repair space: several targeting leaflet coaptation, some focused on the mitral annulus, and still others attempting chordal repair and replacement. But as early results start to trickle in, experts are starting to ask which niche each will fill, how many approaches are needed, and whether combinations of different devices will ultimately be needed to compete with surgical repair.

Giving an overview of the current mitral “device landscape” at TVT 2017, Gregg Stone, MD (Columbia University Medical Center, New York, NY), pointed out that of the 26 companies focused on mitral valve repair—in addition to the at least 28 companies developing transcatheter replacement devices—only one of these, MitraClip (Abbott Vascular) has received US Food and Drug Administration (FDA) approval and just half have been tested in first-in-human or early stage clinical trials.

But if every one of these devices confronts the same hurdles faced by MitraClip, progress may grind to a halt. As Stone pointed out, the COAPT trial, designed to test MitraClip in functional mitral regurgitation (MR) has struggled with monumentally slow enrollment. Launched in December 2012, the trial is finally within 10 patients—an estimated two weeks—of reaching its target enrollment of 610 patients. But as Stone showed here, the 84 active sites have been enrolling at a rate of 0.15 patients per site each month.

“Our long national nightmare is almost over,” Stone said. COAPT results are anticipated for the fall of 2018.

Meanwhile, three novel repair devices targeting the different aspects of mitral valve pathology are poised to enter testing in US pivotal, investigational device exemption (IDE)-approved trials, Stone noted. These are the Carillon device (Cardiac Dimensions), which uses distal and proximal anchors along with a “shaping ribbon” to cinch the dilated mitral annulus in functional MR; Cardioband (Edwards Lifesciences/Valtech), a semirigid, posterior, partial annuloplasty ring; and NeoChord DS100 (NeoChord), a transapically delivered suture implanted as artificial chordae tendineae in degenerative MR. All three trials are underway or soon to launch, Stone said.

Waiting in the Wings

There are many other technologies trailing behind these frontrunners that other speakers in the same TVT 2017 session reviewed today.

Saibal Kar, MD (Cedars-Sinai Medical Center, Los Angeles, CA),discussed the status of the devices developed for edge-to-edge repair—the FDA-approved MitraClip as well as Pascal (Edwards Lifesciences), noting that novel aspects of the still-investigational device include its “spacer” as well as longer, wider paddles.

“If you have a spacer in between and the leaflets coapt over the spacer, like a bridge, then it can be used in cases that are a bit more challenging and potentially treat a broader group of patients,” Kar explained to TCTMD. “The paddles are longer and wider so they can capture a little bit more tissue, so for challenging MitraClip cases, this might be a better solution . . . at least over the current generation MitraClip device.”

A third device, the MitraFlex (TransCardiac Therapeutics), is also exploring this space.

NeoChord, which obtained CE Mark in 2012, has now been used in 600 patients, Adams said. The US IDE trial known as RECHORD was approved in May 2016 and enrollment began last November. As of today, three US centers have currently enrolled over 20 patients, he said. The Harpoon device, which follows a similar method of deployment and anchoring, is currently enrolling patients in it CE Mark trial known as TRACER.

Unlike so-called “minimal MV surgery,” said Adams, transcatheter neochord implantation has the potential to be “truly minimally invasive MV repair” across all patient risk categories. That said, he continued, only pivotal trials comparing outcomes to open surgery “will tell the story.”

A smattering of other companies are also exploring chordal repair/replacement.

Ringing in the Mitral Annulus

The third active area of research in mitral valve repair is direct and indirect annuloplasty. Here, according to Jason Rogers, MD (University of California, Davis), annuloplasty is being explored both as a stand-alone therapy for secondary MR by restricting the annulus size and as a way to improve the durability of primary MR repair by providing annular stabilization. Devices exploring this space include Cardioband, Millipede IRIS (Millipede), and Amend (Valcare)—all direct annular reshaping devices—as well as Carillon, ARTO (MVRx), Accucinch (Ancora), and transcather mitral valve cerclage, all indirect annuloplasty approaches.

While all of these devices are in various stages of early clinical testing, with the Cardioband leading the pack, Rogers predicts that down the road, mitral annuloplasty “will be an essential component of the transcatheter mitral toolbox,’ with both primary and secondary MR patients benefiting from standalone or combination procedures with annuloplasty.”

What About Combination Therapy?

Indeed, the question of combination therapy came up in multiple presentations during today’s morning session since, as yet, it’s not clear which mitral repair technologies will be standalone procedures and if so, in which patient subgroups they may prove most beneficial. Francesco Maisano, MD (University Heart Center, Zurich, Switzerland), a cardiovascular surgeon who has also trained in interventional cardiology, gave the final lecture of the session. It posed the question of whether “combination” transcatheter mitral valve repair techniques represent an unmet need.

In particular, he noted, surgical mitral valve annuloplasty is typically performed in conjunction with surgical edge-to-edge mitral valve repair, with the latter showing reduced durability when performed alone. With degenerative MR, however, some surgeons believe that leaflet repair may be sufficient. Maisano’s prediction is that in the transcatheter arena, while some functional MR patients may benefit from an annuloplasty-only procedure and some degenerative MR patients may benefit from edge-to-edge, most patients regardless of MR etiology may benefit from having a staged or combined approach. That said, “the sequence of interventions,” Maisano concluded, “is an open issue.”

Speaking with TCTMD after the session, Maisano acknowledged that combination procedures face a number of other hurdles including cost/reimbursement, procedure duration, regulatory requirements, and adoption/education.

Simply put, he said, “not all physicians can do both annuloplasty and leaflet repair, so this will take some time.”

He also suggested that transcatheter innovations are to some extent “forcing the indications” since the surgical techniques they are aiming to mimic “were never intended to work as standalone procedures.”

The answer, he believes, is to have much more intensive and varied training in transcatheter mitral valve techniques in the same way that mitral valve surgeons were trained, to allow for expertise across a range of procedures. Given how the mitral repair space is currently divvied up among different, often smaller companies, it’s not likely that funding for this kind of training is going to come any time soon.

Moreover, while the rationale for combination procedures has been raised repeatedly in the past, validation of the concept requires more physicians to know how to do multiple procedures, something unlikely to happen until pivotal trials are done and the devices themselves are commercialized—chicken-or-the-egg phenomenon which Maisano suggested is holding back the field.

Harkening back to Stone’s news about COAPT finally nearing its target enrollment, Maisano, speaking to TCTMD, expressed the hope that other studies will manage to move a little more quickly. One “provocative” possibility is that devices that are essentially mimicking established surgical repair procedures could, in the future, face different regulatory pathways.

“We still have 1 year to understand what happens with COAPT and depending on that outcome, if it is positive, there may be different ways going forward to test new devices,” Maisano said. “But obviously once you demonstrate feasibility and safety, if the device is reproducing a surgical standard it should be easier to approve, rather than another device that is, let’s say, more innovative.”

Photo Credit: Juan Iturriza

Sources

Presentations at: TVT 2017. June 15, 2017. Chicago, IL.

Disclosures

Adams reports grant/research support from Medtronic and NeoChord and royalty income and intellectual property rights with Edwards and Medtronic.

Maisano reports serving as a consultant and receiving research grants from Abbott, Mitraltech, Medtronic, Edwards Lifesciences, St Jude and additional grants from Boston Scientific, Biotronik. He is also the founder of 4Tech, Transseptal Solutions, AFFix, and receives royalties from Edwards Lifesciences. He was also the chief medical officer for Valtech Cardio from 2008 to 2013.

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